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CHAPTER 1 - INTRODUCTION
1.1 Definitions
1.1.1 Antibiotics, antimicrobials, antibacterials, anti-infectives
An antibiotic is defined by Black’s Veterinary Dictionary as “a chemical compound derived from living (or synthesised) organisms which is capable, in small concentrations, of inhibiting the life process of micro-organisms”. The term originally described only those formulations derived from living organisms, but is now applied also to synthetic antimicrobials, such as the sulfonamides.
Black’s Veterinary Dictionary does not distinguish between antibiotics, antimicrobials and antibacterials. However, some authorities define antibiotics more strictly as “substances that kill or slow the growth of bacteria”. The term “antimicrobial” is then broader: these are chemical componds that kill or slow the growth of microbes, including bacteria, protozoa, viruses, fungi and microbial parasites. “Microbe” itself is defined only as “a very small organism”. Antibacterial can be defined as “a substance that kills or slows the growth of bacteria”.
Another widely used term (not least by national industry associations) is “anti-infective”. This is not a technical term and is imprecise. It can be defined as “substances capable of killing infectious agents or of preventing them from spreading and causing infection”.
Unfortunately, data sources for world markets derived from different countries frequently combine different categories that may be variously described as anti-infectives, antibiotics or antimicrobials. These may or may not include antibacterials and anti-protozoals administered in-feed as medicated feed additives (MFAs).
The term “MFA” is also not a precise one. In general terms it refers to antibacterials that are given to livestock in their feed. Some sources include only growth promoters, ie antibacterials applied at sub-clinical doses. Others include anticoccidials; and antibacterials applied as prophylactics to prevent infections (ie not at sub-clinical doses, but not as a curative measure). Some sources may even include all antibacterials applied in-feed to livestock, including those for therapeutic use. In this report, “MFA” refers to medicated growth promoters applied at sub-clinical doses.
Given the above range of definitions and interpretations, the data needs to be interpreted with care in order to avoid invalid comparisons.
The term “antibiotic” has become somewhat debased in recent years, at least in the eyes of the animal health indsutry, as it has been used by non-governmental organisations (NGOs) and the media in a general in a pejorative sense. It has become associated with scare stories about super-bugs and over-intensive livestock farming. The term “antibacterial” is more widely used by the animal health indsutry, and is used in this report.
Antibacterial products may be administered to animals for a number of reasons:
1. therapeutic use: the treatment of active clinical disease caused by susceptible micro-organisms
2. prophylactic use: prevention of disease. This is contentious and believed by many to carry the risk of over-exposure, inducing the development of antimicrobial resistance and limiting future effectiveness of the compound.
3. metaphylactic use: the treatment of animals exposed to infected animals and thought to be incubating the disease or suffering sub-clinical infections and at risk of developing clinical infections if left untreated. The intention being to stop the recycling of infection within a group of animals and reduce overall levels of infection. This approach, if unregulated, can trend towards a purely preventative tactic with the associated risk of resistance. Thus, prudent use guidelines suggest that it should only be undertaken under veterinary supervision after the diagnosis of a disease outbreak and with careful laboratory monitoring of microbial sensitivity to the compound(s) used.
4. growth promotion: administration at low concentrations to increase feed efficiency ie feed conversion, growth rate or yield. The mechanism by which this is thought to occur is debatable; proponents refer to improved efficiency of digestion, opponents believe it results in exposure of gut bacteria to sub-therapeutic concentrations of antibacterials resulting in a risk of bacterial resistance occurring.
1.1.2 Antiprotozoals
Antiprotozoals are antibacterial drugs effective against protozoal diseases, such as coccidiosis in poultry due to the protozoal parasite Eimeria and histomoniasis in turkeys due to Histomonas meleagridis. They are often referred to as anticoccidials (coccidiostats) or antihistomonals. Some antiprotozoals (eg sulphur-based compounds) also have an antibacterial activity. Antiprotozoals are included under the terms antibiotics, antimicrobials and anti-infectives.
In most commercial production units these parasites are endemic and all birds will be exposed to infection. Hence, the chance of clinical outbreaks of disease and production losses from subclinical disease due to coccidiosis or histomoniasis is considered so high that preventative antiprotozoal treatment is generally a standard practice, usually administered as a feed additive.
1.2 Bacteria, viruses and mycoplasmas
Bacterial species involved in a disease process are identified by the collection of samples of contaminated tissues and submitted to a laboratory for culturing and identification through a series of procedures and techniques. Bacteria are broadly divided into two main groups, based upon whether or not they take up a specific stain (Gram stain) when smeared on a microscope slide. Those that do are termed Gram positive (G+); those that don’t Gram negative (G-). Bacteria also differ in their shape when viewed down a microscope, with three main descriptions: rods or bacilli, spheres or cocci, and spirals or spirochaetes (also termed vibrio). Some species grow well in well oxygenated environments (aerobic species), whilst others prefer low levels or an absence of oxygen (anaerobic species), and these preferences need to be accounted for in the laboratory. Finally, different bacterial species often have different metabolic requirements, and metabolic tests (available commercially) form an important component of the identification process.
Antibacterials do not have any direct effect on viral pathogens and their use in outbreaks of clinical disease involving viruses is aimed at combating any secondary infections by opportunistic bacteria which may be present either in the environment or as part of the normal commensal flora of a healthy animal.
Mycoplasmas are small intra-cellular organisms which share some of the characteristics of both bacteria and viruses. These micro-organisms are extremely difficult to culture and work with in the laboratory, requiring special media and being very slow growing. Their role in a number of disease syndromes is being re-evaluated on a regular basis, but several anti-bacterial compounds also have activity against some mycoplasma species.
1.3 Resistance, susceptibility and potency
Antibacterial/antimicrobial resistance (AMR) is considered to occur when bacteria which are normally killed by a particular antibacterial develop the ability to survive when they are exposed to it.
Not all bacteria are sensitive to all antibacterials, for example some antibacterials are only active against G+ species. The term susceptibility is used to describe how sensitive a bacterial population is to a particular antibacterial, and isolates are described as being susceptible/sensitive (S), intermediate (I) or resistant (R).
Generally strains that are identified as being intermediate are progressing towards full resistance. When investigating the sensitivity of bacteria to various drugs, results are often expressed in terms of Minimum Inhibitory Concentration (MIC), ie the minimum concentration of the drug required to inhibit growth of the bacteria. The MIC90 is the minimum concentration of the drug to inhibit growth of 90% of the bacterial isolates tested. Since the different members of any one class of antibacterial act via the same mechanism, it is sufficient to test an isolate against a panel of standard antibacterials representative of each class, in order to determine the sensitivity of that isolate across the different classes of compound available.
The potency of an antibacterial may sometimes be increased by combining it with another compound or another antibacterial, the combination providing an activity greater than the sum of the two separately. Such synergism or potentiation is well known and common examples include the potentiated sulphonamides (eg trimethoprim and sulphadiazine) such as Tribrissen (Schering-Plough); and the combination of clavulanic acid and amoxycillin (Synulox, Pfizer).
Many of the antibacterials used in veterinary medicine were originally developed for, or are derived from compounds used in, human medicine. AMR is a growing problem in both human and veterinary medicine, and there have been calls to limit the use of antibacterials in animals in order to prevent the incidence of AMR increasing in man. Unfortunately, although cross-over and spread of resistant bacteria from animals to man can occur, the cause of the majority of AMR in human infections has its origin in the usage of antibacterials by doctors treating infections in human patients.
Nonetheless, governments with a genuine concern for maintaining the effectiveness of antibacterials in the treatment of human diseases may look to restrict their availability for animal use. It would be a very detrimental step indeed if access by veterinarians to effective compounds were prevented, as the situation prevalent in the pre-antibacterial era would return. Prior to the widespread introduction of antibacterials in the middle of the 20th century, animals with simple infections could often be expected to die. Such cases would include infections of the womb following birth, respiratory infections, neonatal enteric infections and infected wounds. Furthermore, it was only after the advent of antibacterials that it became possible to institute effective control measures for production diseases such as mastitis in dairy cattle. If for no other reason, it is in the interests of animal welfare for these products to remain available.
Diseases in production animals currently requiring the most extensive use of antibacterials are respiratory and enteric infections of growing pigs and calves, mastitis in dairy cows and coccidiosis in poultry. At the present time the world market for antibacterials in production species (ie commercial livestock) is worth more than $3,755 million. The size of the market for production animals is correlated with the medication of groups of animals, with whole batches being treated concurrently. By comparison, the world market for companion animal antibacterials (dogs, cats and horses) where individual animals are treated selectively, is thought to generate annual revenues of around $825 million.
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